Approach
Most patients present with clinical features related to their cytopenias. There are no pathognomonic features, and the diagnosis is established by a complete blood count (CBC) to identify the cytopenias followed by a bone marrow biopsy to establish the cause.[30]
History and examination
Signs and symptoms relating to the cytopenias include:
Infection from leukopenia
Fatigue, pallor, exertional dyspnea, and tachycardia from anemia
Bleeding or easy bruising from thrombocytopenia.
Most cases are idiopathic, but a history suggestive of the presence of known triggers should be sought. These include:
All drug exposures (including nonprescription medications) from 6 months to 1 month before symptom onset. Known causative agents include chloramphenicol and nonsteroidal anti-inflammatory drugs (NSAIDs). Other drugs and exposures with a weak association to AA, which may be coincidental, include penicillamine, gold therapy, and benzene exposure.[2][3]
Occupational exposure to chemicals or pesticides associated with AA.
Recent history of jaundice or hepatitis or other viral illness.
Detailed/extended family history of AA, myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), and lung/liver fibrosis.
Physical exam should be normal except for the sequelae of cytopenias (pallor, ecchymoses, any ongoing infection). Splenomegaly found on examination or imaging is not a typical feature of AA and should prompt suspicion of other causes, including malignancy (lymphoma, myeloproliferative diseases), mycobacterial infection, and sepsis.
Rarely, clinical features of an inherited syndrome may be present. Suspicion should be prompted if the patient presents at a young age, or if specific associated clinical signs are present. Patients with congenital AA most commonly present in early childhood, but can sometimes present as young adults, occasionally in their 30s or 40s, and, very rarely, in their 50s.
Fanconi anemia may be suggested by the following:[4]
Pigmentation abnormalities (most classically cafe au lait spots)
Hearing defects, usually conductive hearing loss
Macrocytosis
Renal abnormalities: double ureters, renal hypoplasia, unilateral renal aplasia, horseshoe kidneys
Male genital abnormalities: hypospadias, hypogenitalia, undescended testes, and infertility
Female genital abnormalities: underdeveloped genitalia, uterine anomalies
Solid tumors occurring at an unusually young age
Short stature.
Dyskeratosis congenita may be suggested by the following:[5]
Nail malformations, reticular rash, premature hair loss, premature graying
Hyperhidrosis, epiphora
Oral leukoplakia, extensive dental caries or tooth loss
Esophageal strictures
Liver abnormalities (e.g., cirrhosis, noncirrhotic portal hypertension, cryptic liver disease)
Pulmonary fibrosis/familial pulmonary fibrosis
Osteoporosis, avascular necrosis of bone.
Shwachman-Diamond Syndrome may be suggested by the following:[6]
Pancreatic insufficiency
Liver abnormalities (elevated liver function tests)
Skeletal dysplasia.
GATA2-related disorders may be suggested by the following:[7][8]
Persistent warts
Monocytopenia
Nontuberculous mycobacterial infections
Pulmonary alveolar proteinosis
Congenital lymphedema, deafness, and MDS (Emberger syndrome)
Immunodeficiency (DCML [dendritic cell, monocyte, B cell, and NK cell deficiency]).
Investigations
Initial laboratory testing should include CBC with manual differential to define the pancytopenias and reticulocyte count, with the following findings suggesting AA:
Hemoglobin <10 g/dL
Platelet count <50 × 10⁹/L
Absolute neutrophil count <1.5 × 10⁹/L
Corrected reticulocyte percentage <1% or absolute reticulocyte count <20 × 10⁹/L (<60 × 10⁹/L using an automated analysis).
Once pancytopenias are demonstrated in ≥2 cell lines, bone marrow biopsy and cytogenetic analyses are required to establish the diagnosis and exclude malignancy. AA is characterized by a hypocellular marrow, which distinguishes it from most other malignant causes of pancytopenia (e.g., leukemia, lymphoma, myeloma, metastatic solid tumor). The absence of significant dysplasia or fibrosis, blasts, and clonal abnormalities also helps to rule out MDS. Hypoplastic MDS can be challenging to distinguish from AA, but this can usually be done on careful review of the bone marrow biopsy.[31]
Flow cytometry for glycosylphosphatidylinositol (GPI)-anchored proteins is used to test for paroxysmal nocturnal hemoglobinuria (PNH).
All patients should be tested for HIV, serum vitamin B12 levels, and serum folate levels, as they are relatively common differential diagnoses. Testing for other disorders associated with pancytopenia may be pursued in parallel with bone marrow biopsy if there are signs or symptoms other than those referable to the cytopenias, or if medical history or physical findings raise concerns.
If a congenital syndrome is suspected, appropriate diagnostic tests include:
Chromosomal breakage testing for Fanconi anemia
Relevant genetic sequencing for the other disorders such as TERC, TERT, TINF 2, DKC1 (for dyskeratosis congenita), SBDS (for Shwachman-Diamond Syndrome), ribosomal proteins (for Diamond-Blackfan anemia), and GATA2 (for inherited GATA2-related disorder)
Telomere length may be measured to rule out telomeropathies, although this test is not routinely available in many centers.[5]
Inherited marrow failure syndrome gene panels with next-generation sequencing are available at some specialist centers. They can be used to identify telomeropathies, mutations, and malignancies.
Imaging
A chest x-ray can be ordered if malignancy, infection, or lung fibrosis is suspected.
An abdominal ultrasound can be ordered if malignancy, Fanconi anemia, or a telomeropathy is suspected. Splenomegaly or lymphadenopathy suggests a hematologic malignancy rather than AA. Abnormal or displaced kidneys may be seen in Fanconi anemia. Liver cirrhosis/fibrosis may suggest telomeropathies.[5]
A computed tomography scan can be ordered if telomeropathies or dyskeratosis congenita is suspected. Lung fibrosis, cirrhosis, or noncirrhotic portal hypertension may suggest dyskeratosis congenita.
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